N&#39;-cyclopropyl ethylenediamine derivatives



United States Patent 01 Efice US. Cl. 260-326.9 3 Claims ABSTRACT OF THEDISCLOSURE N' Cyclopropyl ethylenediamine derivatives and thepharmaceutically acceptable nontoxic salts thereof are useful asantidepressants and monoamine oxidase inhibitors in mammals.

CROSS-REFERENCE TO RELATED APPLICATIONS This application is acontinuation-in-part of application Ser. No. 454,972, filed May 11,1965, now US. Pat. No. 3,365,458, which is a continnation-in-part of nowabandoned application Ser. No. 377,387, filed June 23, 1964.

BACKGROUND OF THE INVENTION Field of the invention This inventionrelates to novel compounds. More particularly, this invention relates tonovel compounds which possess valuable therapeutic utility asantidepressants and monoamine oxidase inhibitors, and to intermediatesuseful in the preparation theroef. In another aspect, this inventionrelates to a novel method of treating depression.

Description of the prior art There exists a need to provide additionalagents useful as antidepressants and monoamine oxidase inhibitors. Thusit is an object of this invention to provide a new class of compoundshaving antidepressant activity. Another object of the present inventionis to provide novel compounds which inhibit the enzyme monoamineoxidase. It is a still further object of the present invention toprovide a novel method of treating depression.

SUMMARY OF THE INVENTION The above and other objects which may appear asthe specification proceeds are achieved by this invention whichcomprises the provision of compounds selected from the group consistingof compounds having the formula R(Y)NCH2OH2-N and the pharmaceuticallyacceptable nontoxic salts thereof. In Formula I, R is a member selectedfrom the group consisting of (lower) alkynyl, thienyl, furyl, pyridyl,pyrrolyl, naphthyl and Ph-, wherein Ph is a radical of the formula (II)R4 wherein R and R are each a member selected from the group consistingof hydrogen, chloro, bromo, iodo,

Patented Oct. 6, 1970 fluoro, trifluoromethyl, (lower)alkyl,(lower)alkoxy, (lower)alkylthio, di(lower)alkylsulfamyl, phenyl,phenoxy, benzyl, and when taken together, methylenedioxy; R and R may bethe same or different in each occurrence;

n is a whole integer from 0 to 1 inclusive;

R is a member selected from the group consisting of hydrogen,(lower)alkyl, (1ower)alkenyl, (lower)alkynyl, and cycloalkyl radicalshaving from 3 to 7 carbon atoms, inclusive, e.g. cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl;

R is a member selected from the group consisting of hydrogen,(lower)alkyl, (lower)alkenyl, (lower)alkynyl, phenylalkyl, wherein thealkyl moiety contains from 1 to 4 carbon atoms, inclusive, andphenylalkenyl, wherein the alkenyl moiety contains from 1 to 4 carbonatoms, inclusive;

R is a member selected from the group consisting of hydrogen,(lower)alkyl, (lower)alkenyl, (lower)alkynyl, Ph-, Ph-a1k-, andPh-alken-, in which Ph is as represented above, alk represents adivalent alkylene radical containing from 1 to 4 carbon atoms,inclusive, and

Y is a member selected from the group consisting of (lower)alkylene,(lower)alkenylene, (lower) alkynylene, oxy(lower)alkylene andmercapto(lower) alkylene.

DETAILED DESCRIPTION The pharmaceutically acceptable nontoxic saltsinclude the organic and inorganic monoand diacid addition salts, e.g.,those prepared from acids such as hydrochloric, sulfuric, sulfamic,tartaric, fumaric, hydrobromic, hydroiodic, glycolic, citric, maleic,phosphoric, succinic, acetic, nitric, and the like.

The term (lower)alkyl as used herein means both straight and branchedchain alkyl radicals containing from 1 to 8 carbon atoms, e.g., methyl,ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, amyl, hexyl,2-ethy1- hexyl, etc.

The term (lower)alkenyl as used herein means both straight and branchedchain alkenyl radicals containing from 2 to 8 carbon atoms, e.g.,ethenyl, allyl, l-propenyl, 1 butenyl, 3 butenyl, 2 methyl-l-propenyl,3-pentyl-1- hexenyl, 7-octenyl, etc.

The term (lower)alkynyl as used herein means both straight and branchedchain alkynyl radicals containing from 2 to 8 carbon atoms, e.g.,ethinyl, propargyl, 1- butinyl, Z-butinyl, l-l-dimethylpropargyl,l-pentinyl, 1- heptinyl, etc.

The term (lower)alkylene as used herein means both straight and branchedchain alkylene radicals containing from 1 to 8 carbon atoms, e.g.,methylene, ethylene, octylene, propylene, butylene, isobutylene,t-butylene, amylene, hexylene, Z-ethyl-hexylene, etc.

The term (lower)alkenylene as used herein means both straight andbranched chain alkenylene radicals containing from 1 to 8 carbon atoms,e.g., ethenylene, l-propenylene, 3 butenylene, 2-methyl-1-l-buteny1ene,etc.

The term (lower)alkynylene as used herein means both straight andbranched chain alkynylene radicals containing from 1 to 8 carbon atoms,e.g., ethinylene, propargylene,l-propinylene, 3-butinylene,1,1-dimethyl- 3-butinylene, hexinylene, octinylene, etc.

Similarly, where the terms (lower) is used as part of the description ofanother group, e.g., (lower)alkoxy, it refers to the alkyl portion ofsuch group which is therefore as described in connection With (lower)alkyl.

1 9 Specific results for the testing of individual compounds are givenin the following tables.

TABLE I.--ANTI-INFLA1\IMATO RY ACTIVITY [Inhibition of endotoxin-inducedlung inflammation] Dose, Percent mg./kg. Route inhibition Compound ofExample No.:

B4 100 p.o. 24

1 Oral (p.o.); subcutaneous (s.c.).

TABLE IL-ANTI-SE C RETO RY ACIIVII Y Percent dilIerence Dose, in lug/kg.acidity Compound of example No.:

134 25 54 100 88 B11 6. 25 31 100 77 B12 25 49 100 64 B13 50 28 100 49B14 50 51 200 100 B15 25 94 85 100 42 94 25 100 26 100 83 40 14 33 31-51 25 68 Dose, Percent Jug/kg inhibition I 01mm: 1. A compound of theformula HO R Q OYN=B wherein N=B is a member of the group consisting ofdi-lower-alkylamino, dicycloalkylamiuo in which the cycloalkyl has from5 to 6 ring members and a total of from five to nine carbon atoms,N-(cycloalkyl)-loweralkylamino in which the cycloalkyl has from 5 to 6ring members and a total of from five to nine carbon atoms,polymethylenimino having from 5 to 7 ring members and a total of fromfive to nine carbon atoms, 4-morpholinyl, l-piperazinyl,4-methyl-l-piperazinyl, 4-phenyl-1-piperazinyl,di-(phenyl-lower-alkyl)amino, andN-(phenyl-loweralkyl)-lower-alkylamino; Y is a lower-alkyene bridgehaving its connecting valences on different carbon atoms; R is hydrogen,lower-alkyl, phenyl or phenyl-lower-alkyl, wherein phenyl isunsubstituted or is substituted by from one to three groups selectedfrom lower-alkyl, loweralkoxy, and halogen, or one group selected fromloweralkylthio, lower-alkylsulfinyl, lower-alkylsulfonyl, trifluoromethyl, and trifluoromethoxy; X is O, S or S0 and Q and Q representhydrogen or from one to three groups selected from lower-alkyl,lower-alkoxy, and halogen, or one group selected from lower-alkylthio,lower-alkylsulfinyl, lower-alkyl sulfonyl, trifiuoromethyl, andtrifluoromethoxy.

2. A compound according to claim 1 wherein R is monocarbocyclicaryl-lower-alkyl, Q and Q are hydrogen and the basic side chain is inthe 3-position.

3. A compound according to claim 2 wherein N=B is di-lower-alkylamino, Qand Q are hydrogen and the basic side chain is in the 3-position.

4. 3-(Z-dimethylaminoethoxy)9-benzyl 9 thioxan thenol, according toclaim 3 wherein N=B is dimethylamino, Y is ethylene, R is benzyl and Xis S.

5. 3 (2-dimethylaminoethoXy)-9-ethyl 9 thioxanthenol according to claim1 wherein N=B is dimethylamino, Y is ethylene, R is ethyl, X is S, Q andQ are hydrogen and the basic side chain is in the 3-position.

6. 3-(2-diethylaminoethoxy) 9-benzyl 9' thioxanthen- 01, according toclaim 3 wherein N=B is diethylamino, Y is ethylene, R is benzyl and X isS.

7. 2-(Z-dimethylaminoethoxy)9-benzyl 9 thioxanthenol, according to claim1 wherein N=B is dimethylamino, Y is ethylene, R is benzyl, X is S, Qand Q are hydrogen and the basic side chain is in the 2-position.

8. 3-[2-( 1-pyrrolidy1)ethoxy]9-benzyl 9 thioXanthenol, according toclaim 2 wherein N=B is l-pyrrolidyl, Y is ethylene, R is benzyl and X isS.

9. 3-(3-dimethylaminopropoxy)9-benzyl 9 thioxanthenol, according toclaim 3 wherein N=B is dimethylamino, Y is propylene, R is benzyl and Xis S.

10. A compound according to claim 1 wherein R is hydrogen and Q and Qare hydrogen.

11. 3(2-dimethylaminoethoxy) 9 thioxanthenol, a compound according toclaim 10 wherein N=B is dimethylamino, Y is ethylene, X is S and thebasic side chain is in the 3-position.

12. 2-(2-dimethylaminoethoxy) 9 thioxanthenol, a compound according toclaim 10 wherein N=B is dimethylamino, Y is ethylene, X is S and thebasic side chain is in the 2-position.

13. 2 (3-dimethylaminopropoxy)9-thioXanthenol, a compound according toclaim 10 wherein N B is dimethylamino, Y is propylene, X is S and thebasic side chain is in the 2-position.

No references cited.

ALEX MAZEL, Primary Examiner J. TOVAR, Assistant Examiner US. Cl. X.R.

pooled for each determination, and the compound was administered orally.The level of brain amines was determined at different intervals afteradministration, and a control group was run in each experiment.

The results for a preferred compound of the present invention, Nbenzyl-N-methyl-N'-cyclopropylethylenediamine, are summarized in thefollowing table and show that the compound is a potent elevator of brainamines, and is, therefore, a powerful antidepressant agent.

Percent increase in Concentration over control Time after Dose, mgjkg.drug, hours Nolepinephrine Serotonin The results for another preferredcompound of the present invention, N-methyl-N-propargyl-N-cyclopropyl-N'-benzyl ethylenediamine dihydrochloride, are summarized in thefollowing table and show that the compound is a potent elevator of brainamines, and is, therefore, a powerful antidepressant agent.

Brain amine levelpercent The compounds of this invention are alsocapable of preventing the sedative effects of reserpine in mice. Oraladministration of as little as mg./kg. of a preferred compound of thepresent invention, N-benzyl-N-methyl- N-cyclopropylethylenediamine, inmice three hours before intravenous administration of 5 mg./kg. ofreserpine completely prevented symptoms usually associated withreserpine administration, i.e. increased motor activity, profusesalivation, and ptosis. Thus, the preferred compound of the presentinvention is a powerful monoamine oxidase inhibitor, and exhibits markedantidepressant activity. N-benzyl-N-methyl-N'-cyclopropylethylenediamineexhibited an oral LD in mice of 849 mg./ kg.

Another preferred compound, N-methyl-N-propargyl- N'-benzyl-N'cyclopropylethylenediamine dihydrochloride, had a minimum effective doseof 10 mg./kg. and an oral LD in mice of 420 mg./kg.

The compounds of the present invention are prepared by the acylation ofa primary or a secondary cyclopropylamine of the formula (XXIV) R3wherein H and R are as represented above with an whaloacetylhalide or ana-tosylacetylhalide of the formula (XXV) H wherein X is chloro, bromo,iodo, fluoro, or tosyl, and Z is chloro, bromo, iodo, or fiuoro, in thepresence of an acid acceptor such as potassium carbonate, pyridine,triethylamine or sodium hydroxide in an aqueous acetone or benzenesolution to yield an N'-cyclopropyl oc-hfllO- or tosylacetamide of theformula (XXVI) R3 wherein X, R and R are as represented above. Thisprocedure is generally described in US. Pat. No. 2,569,288.

Representative of the primary cyclopropylamines which may be used inthis process are,

cyclopropylamine,

fi-methylcyclopropylamine, fl-ethylcyclopropylamine,fi-allylcyclopropylamine, fl-propargylcyclopropylamine,fl-phenylcyclopropylamine,

[3 para-trifluoromethylphenylcyclopropylamine,,B-para-ehlorophenylcyclopropylamine,,B-para-ethoxyphenylcyclopropylamine,5-3,4-methylenedioxyphenylcyclopropylamine andli-para-methylthiophenylcyclopropylamine.

Representative of the secondary cyclopropylamines which may be employedare,

N-cyclopropyl-N-methylamine,

N-cyclop ropyl-N-isopropylamine,

N-cyclopropyl-N-allylamine,

N-cyclopropyl-N-prop argylamine,

N-cycloprop yl-N-benzylamine,

N-cyclopropyl-N-phenylisopropylamine,

N-cyclopropyl-N-cinnamylamine,

N-B-phenylcyclopropyl-N-methylamine,

N-flm-trifluoromethyl phenylcyclopropyl-N-methylamine,

N-B- (pfiuoro phenylcyclopropyl-N-allylamine,

N-,8- (m,p-methylenedioxy phenylcyclopropyl-N-propargylarnine and IN-fi- (o-methylmercapto phenylcyclopropyl-N-benzylamine.

Some of the a-haloor tosylacetamide halides which may be used in thisprocess are,

a-chloroacetyl chloride, a-bromoacetyl chloride, a-iodoacetyl bromideand a-para-tosylacetyl chloride.

Some of the N-cyclopropyl a-haloor tosylacetamides thus formed are,

N-cyclopropyl a-chloroacetamide,

N-Z-methylcyclopropyl a-bromoacetamide,

N-Z-phenylcyclopropyl a-iodoacetamide,

N-Z-allylcyclopropyl u-chloroacetamide,

N-Z-propargylcyclopropyl tit-tosylacetamide,

N-Z- m-trifluoromethyl) phenylcyclopropyl Ot-ChlOIO- acetamide,

N-2-(p-fluoro)phenylcyclopropyl a-bromoacetamide,

N-Z-(o-bromo)phenylcyclopropyl a-chloroacetamide,

N-2(p-ethoxy)phenylcyclopropyl a-bromoacetamide,

N-2- (m,p-me-thylenedioxy) phenylcyclopropyl a-chloroacetamide,

N-2- (o-methylmercapto phenylcyclopropyl a-chloroacetamide,

N-cyclopropyl-N-methyl tx-bromoacetamide,

N-cyclopropyl-N-isopropyl a-bromoacetamide,

N-cyclopropyl-N-benzyl a-bromoacetamide,

N-2-methylcyclopropyl-N-allyl oebromoacetamide,

N-2-phenylcyclopropyl-N-propargyl u-iodoacetamide,

N-2- (rn-trifluoromethyl) phenylcyclopropyl-N-propargyl a-iodoacetamide,

N-2-allylcyclopropyl-N-methyl wbromoacetamide,

I N-Z-(p-fluoro)phenylcyclopropyl-N-benzyl oc-bIOIllO- acetamide, Ncyclopropyl-N-propargyl a-bromoacetamide, N-Z-phenylcyclopropyl-N-methylot-bromoacetamide, N-Z-(o-chloro) phenylcyclopropyl-N-methyl u-bromoacetamide and N-2- (o-methyl phenylcyclo propyl-N-pro par gylu-bromoacetamide.

The N-cyclopropyl a-haloor tosylacetamides are converted toN-cyclopropylglycinamides of the formula (XXVII) aniline,m-trifiuoromethylaniline, o-bromoaniline, o-methylaniline,p-propargyloxyaniline, p-ethoxyaniline, m-methoxyaniline,o-methylmercaptoaniline, benzylamine, a-methylbenzylamine,a-isopropylbenzylamine, o-chlorobenzylamine, p-fluorobenzylamine,m-trifluoromethylbenzylamine, o-rnethylmercaptobenzylamine,p-ethoxybenzylamine, p-propargyloxybenzylamine,m,p-methy1enedioxybenzylamine, p-phenoxybenzylamine,p-phenylbenzylamine, p-dialkylsulfamylbenzylamine, a-naphthylamine,fl-naphthylamine, a-naphthylmethylamine, B-naphthylmethylamine,phenylisopropylamine, p-fluorophenylisopropylamine,m-trifluoromethylphenylisopropylamine, p-ethoxyphenylisopropylamine,o-methylmercaptophenylisopropylamine, o-methylphenylisopropylamine,a-thienylmethylamine, p-thienylmethylamine, 2-furfurylmethylamine,2-pyridylmethylamine, 3-pyridylmethylamine, 4-pyridylmethylamine,2-pyridylethylamine, 3-pyridylethylamine, 4-pyridylethylamine,l-pyrrolylrnethylamine, propargylamine,

ethinylamine and butinyl.

Some of the secondary amines which may be used in this step of theprocess are,

N-phenyl-N-methylamine, N-phenyl-N-propargylamine,N-phenyl-N-allylamine, Nphenyl-N-cyclopropylamine,N-phenyl-N-cyclobutylamine, N-phenyl-N-cyclopentylamine,N-benzyl-N-rnethylamine, N-benzyl-N-allylamine,N-benzyl-N-propargylamine, N-benzyl-N-cyclopropylamine,N-benzyl-N-cyclobutylamine, N-benZyl-N-cyclopentylamine,N-benzyl-N-cycloheptylamine, N-benzyl-N-cyclooctylamine,N-p-ethoxyphenyl-N-methylamine, N-p-chlorophenyl-N-methylamine,N-o-bromophenyl-N-methylamine, N-m-trifluoromethylphenyl-N-methylamine,N-3,4-methylenedioxyphenyl-N-methylamine,N-o-methylmercaptophenyl-N-methylamine,N-p-dialkylsulfamylphenyl-N-methylamine, N-o-methylphenyl-N-methylamine,N-o-methylbenzyl-N-methylamine, N-o-bromobenzyl-N-methylamine,N-p-fluorobenzyl-N-methylamine, N-m-trifluoromethylbenzyl-N-methylamine,N-p-ethoXybenzyl-N-methylamine, N-p-propargyloxybenzyl-N-methylamine,N-p-phenoxybenzyl-N-methylamine, N-p-phenylbenzyl-N-methylamine,N-3,4-methylenedioxybenzyl-N-methylamine,N-o-methylmercaptobenzyl-N-rnethylamine,N-p-dialkylsulfamylbenzyl-N-methylamine,N-o-methylbenzyl-N-propargylamine, N-o-bromobenzyl-N-propargylamine,N-p-fiuorobenzyl-N-propargylamine,N-m-trifluoromethylbenzyl-N-propargylamine,N-p-ethoxybenzyl-N-propargylamine,N-p-propargyloxybenzyl-N-propargylamine,N-p-phenoxybenzyl-N-propargylamine, N-p-phenylbenzyl-N-propargylamine,N-3,4-methylenedioXybenzyl-N-propargylamine,N-o-methylmercaptobenzyl-N-propargylamine,N-p-dialkylsulfamylbenzyl-N-propargylamine, N-methyl-N-propargylamine,N-ethyl-N-propargylamine, N-isopropyl-N-propargylamine,N-allyl-N-propargylamine, N-butenyl-N-propargylamine,N-propargyl-N-propargylamine, N-cyclopropyl-N-propargylamine,N-methyl-N-ethinylamine and N-methyl-N-butinylarnine.

Conversion of the N'-cyclopropylglycinamides to the ethylenediamines ofthis invention having the formula (XXVIII) this invention which may beproduced in the foregoing manner are,

N-phenyl-N'-cyclopropylethylene diamine,

N-phenyl-N-methyl-N'-cyclopropylethylenediamine,

N-phenyl -N-propargyl-N-cyclo pro pylethylenediamine,

N-phenyl-N-'benzyl-N-cyclopropylethylenediamine,

N- (m-trifluoromethylphenyl)-N-cyc1opropyl-N-cyclopropyl-N'-methy1ethylenedi amine,

N- (p-chlorophenyl -N-propargyl-N'- Z-phenylcyclopropyl)-N'-propargylethylenediamine,

N- (p-ethoxyphenyl) -N-cinnamyl-N'- 2-methylcyclopro pyl)-N-B-phenethylethylenediamine,

N-benzyl-N'-cyclopropylethylenediamine,

N-benzyl-N-methyl-N'-cyclopropylethylenediamine,

N -b enzyl-N-allyl-N-cyclo pro pylethylenediamine,

N-benzyl-N-propargyl-N'-cyclopropylethylenediamine,

N-benzyl-N-cyclopropyl-N-cyc1opropylethylenediamine,

N-benzyl-N-cyclop ropylmethyl-N'-cyclopro'p ylethylenediamine,

N-o-chlorobenzyl-N-methyl-N'-cyclopropylethylenediamine,

N-m-trifluoromethyl-N-methyl-N'-cyclopropyl-N'-propargylethylenediamine,

N-p-ethoxybenzyl-N-methyl-N'-cyclopropyl-N-methylethylenediamine,

N-o-methylmercaptobenzyl-N-Inethyl-N-cyclopropyl-N-propargylethylenediamine,

N-p-phenoxyb enzyl-N-methyl-N'-cyclop ropyl-N'-,B-

phenethylethylenediamine,

N-p-phenylbenzyl-N-allyl-N'-2-methylcyclopropyl-N'-cinnamylethylenediamine,

N-benzyl-N-methyl-N-2-phenylcyclopropylethylenediamine,

N-benzyl-N-methyl-N-Z- (m-trifluoromethylphenyl)cyclopropylethylenediamine,

N-benzyl-N-methyl-N'-2- (o-chlorophenyl cyclopropylethylenediamine,

N b enzyl-N-methyl-N-2-phenylcyclopropyl-N'-methy1- ethylenediamine,

N-benZyl-N-methyl-N'-2-phenylcyclopropyl-N'- propargylethylenediamine,

N-benzyl-N-methy1-N-cyclopropyl-N-cinnamylethylenediamine,

N-benzyl-N-methyl-N',N'-bis-cyclopropylethylenediamine,

N-(4-diethylsulfamylbenzyl) -N-methyl-N'-cyclopropylethylenediamine,

N-cinnamyl-N-methyl-N-cyclop ropylethylenediamine,

N-a-methylphenethyl-N-methyl-N'-cyc1opropylethylenediamine,

N-a-methyl-fi-phenoxyethyl-N-methyl-N'-cyc1opropylethylenediamine,

N-methyl-N-propargly-N-benzyl-N'-cyclopropylethylenediamine,

N-methyl-N-p ropargyl-N'-benzyl-N-,8-methylcyclopropylethylenediamine,

N-methyl-N-propargyl-N' benzyl-N'-,B-allylcyclopropylethylenediamine,

N-methyl-N-prop ar gyl-N'-benzyl-N'-13-phenylcyclopropylethylenediamine,

N-methyl-N-propargyl-N'-phenyl-N'-cyclopropylethylenediamine,

N-ethyl-N-prop argyl-N'-benzyl-N-cyclopropylethylenediamine,

N-isopropyl-N-propargyl-N-benzyl-N'-cyclop ropylethylenediamine,

N-allyl-N-propargyl-N-benzyl-N-cyclopropylethylenediamine,N-butenyl-N-propargyl-N-benzyl-N'-cyclopropylethylenediamine,N-propargyl-N-propargyl-N'-benzyl-N'-cyclopropylethylenediamine,N-cyclopropyl-N-propargyl-N'-benzyl-N'-cyclopropylethylenediamine,

N-methyl-N-butinyl-N'-benzyl-N'-cyclopropylethylenediamine,N-methyl-N-ethinyl-N'-benzyl-N-cyclopropylethylenediamine,N-propargyl-N'-cyclopropylethylenediamine, N-propargyl-N'benzyl-N'-cyclopropylethylenediamine andN-methy1-N-propargyl-N'-cyclopropylethy1enediamine.

The tertiary cyclopropylethylenediamines of Formula XXVIII but wherein Ris other than hydrogen, may also be produced by reacting a secondarydiamine such as N- benZyl-N-Inethyl N cyclopropylethylenediamine with areactive alkyl, alkenyl, alkynyl, aralkyl, aralkenyl or aralkynyl halidein the presence of an acid acceptor such as triethylamine, potassiumcarbonate and an inert solvent such as benzene or toluene; and thenmethylating the secondary amine with formaldehyde and formic acid.

The tertiary ethylenediamines of this invention may also be produced byreacting a secondary diamine such as Nmethyl-N-benzyl-N'-cyclopropylethylenediamine with a Grignard reagentsuch as methylmagnesium bromide and allowing the resulting magnesiumamide salt to interact 'with a reactive halide such as propargylbromide. This method may be carried out according to the followingreaction scheme:

+ CHa-MgBr CH3 I Hz CH CH2 An alternate process of forming the diaminesof Formula I consists of forming an a-haloacetamide of the formula(XXIX) (XXX) R1 R2 wherein R, Y, n, R R and R are as represented above.The glycinamide of Formula XXX may then be reduced with lithium aluminumhydride or sodium borohydride to the desired ethylenediamine of FormulaI.

The starting materials used in the processes described herein arecompounds which are either commercially 11 available, well-known in theart, or easily prepared in accordance with standard organic procedurespreviously described in the chemical literature.

For example, the preparation of various cyclopropylamines is describedin J. Med. Pharm. Chem. (6), 12431265, (1962), U.S. Pat. Nos. 3,079,403.3,081,336 and 3,083,226; British Pat. No. 913,898; and Canadian Pat. No.685,776, etc.; and the preparation of various propargylamines isdescribed in J. Med. Chem. 7, 390 (1964).

The compounds of this invention may be administered as the free bases orin the form of their nontoxic addition salts. They may be compounded andformulated into pharmaceutical preparations in unit dosage form for oralor parenteral administration with organic or inorganic solid materialsor liquids which are pharmaceutically acceptable carriers. Thecompositions may take the form of tablets, powder granules, capsules,suspensions, solutions and the like. Such compositions are consideredwithin the scope of this invention.

The compositions of this invention when administered orally orparenterally, in an effective amount, are effective in the treatment ofdepression and for monoamine oxidase inhibition. The usual dosage isfrom to 200 mgm./kg., although lesser or greater quantities may be used.

The following examples are intended to illustrate the inventiondescribed herein without unduly restricting it.

EXAMPLE 1 Preparation of N-cyclopropyl a-chloroacetamideCyclopropylamine (70 gm., 1.23 mol) was added to 150 ml. water andcooled in an ice-water bath. To the stirred mixture was added dropwiseand simultaneously 113 gm. (1.23 mol) zx-Cl'llOl'OflCfitYl chloride andan aqueous solution containing 50 gm. of sodium hydroxide. The amideseparated as a white solid and was collected by filtration. The solidwas taken up in methylene chloride and dried with Na SO Removal of thesolvent yielded 131 gm. of N'-cyclopropyl a-chloroacetamide having amelting point of 81-84 C., and an infrared absorption spectrum asfollows:

EXAMPLE 2 Preparation of N'-benzyl-N'-cyclopropy1 a-chloroacetamide Amixture of 29 gm. (0.2 mol) of N-benzyl-N-cyclopropylamine and 65 m1. ofwater was cooled in an ice bath with good stirring. a-chloroacetylchloride (34 gm., 0.3 mol), and 8 gm. (0.2 mol) of NaOH in an equalvolume of water were added simultaneously and dropwise to the cold aminesolution. When the addition was completed, stirring was continued foranother 30 minutes and the solution was extracted with ether. Theethereal solution was washed twice with 10% NaOH, then water, dried withMgSO and filtered. Removal of the ether in vacuo yielded a residue whichwas fractionally dis tilled. Yield gm., B.P. 128130/0.15 mm. Hg

KER? 3.08 and 6.08

12 EXAMPLE 3 Preparation of N-2-phenylcyclopropyl a-chloroacetamideZ-phenylcyclopropylamine (1.23 mol) was added to ml. water and cooled inan ice water bath. To the stirred mixture was added dropwise andsimultaneously 113 gm. (1.23 mol) a-chloroacetyl chloride and an aqueoussolution containing 50 gm. of sodium hydroxide. The amide separated as awhite solid and was collected by filtration. The solid was taken up inmethylene chloride and dried with Na SO Removal of the solvent yieldedN-2-phenylcyclopropyl oc-chloroacetamide.

EXAMPLE 4 When, in the procedure of Example 1, the cyclopropylamine isreplaced by an equal molar amount of Z-methylcyclopropylamine,2-ethylcyclopropylamine, 2-isopropylcyclopropylamine,2-phenylcyclopropylamine, 2-benzylcyclopropylamine,2-4-chlorophenylcyclopropylamine,2-4-trifluoromethylphenylcylcopropylamine,2-4-methylphenylcyclopropylamine, 2-2-fiuorophenylcyclopropylamine,

2-3 -methylphenyclyclopropylamine,

2-3 -bromophenylcyclopropylamine, 2-2,6-dichlorophenylcyclopropylamine,2-4-methylthi0phenylcyclopropylamine,2-2-dimethylsulfamylphenlycyclopropylamine,2-2-iodo-4-methylphenycyclopropylamine,2-4-isopropylphenylcyclopropylamine, 2-4-phenylphenylcyclopropylamine,

2-3 -phenoxyphenylcyclopropylamine, 2-4-benzylphenylcyclopropylamine,2-3,4-methylenedioxyphenylcyclopropylamine,2-4-fluorophenylcyclopropylamine,2-4-chlorobenzylphenylcyclopropylamine, 2-phenethycyclopropylamine,2-allylcyclopropylamine, 2-propargylcyclopropylamine,

2-1-butinyl cyclopropylamine, Z-ethinylcyclopropylamine,2-ethenylcyclopropylamine, 2-1-propenylcyclopropylamine,2-3-butenylcyclopropylamine, 2-1-hexeny1cyclopropylamine,2-phenylisopropylcyclopropylamine, 2-4-phenoxypheny1cyclopropylamine,2-cinnamylcyclopropylamine, 2-2,4-dimethylphenylcyclopropylamine and2-4-trifiuoromethylcinnamylcyclopropylamine,

there are obtained,

N-2-methylcyclopropyl u-chloroacetamide, N '-2-ethylcycl0propylu-chloroacetamide, N'-2-isopropylcyclopropyl a-chloroacetamide,N-2-phenylcyclopropyl a-chloroacetamide, N'-2-benzy1cyclopropyla-chloroacetamide, N'-2-4-chlorophenylcyclopropyl a-chloroacetamide,-N-2-4-trifluoromethylphenylcyclopropyl a-chloroacetamide,N-2-4-methylphenylcyclopropyl a-chloroacetamide,N'-2-2-fiuorophenylcyclopropyl a-chloroacetamide,N'-2-3-rnethylphenylcyclopropyl a-chloroacetamide,N-2-3-bromophenylcyclopropyl a-chloroacetamide, N-2-2,6-dichlorophenylcyclopropyl ot-chloroacetamide,N-2-4-methylthiophenylcyclopropyl tx-chloroacetamide,N-2-2-dimethylsulfamylphenylcyclopropyl a-chloroacetamide,

EXAMPLE When, in the procedure of Example 2, N'-benzyl-N'-cyclopropylamine, is replaced by an equal molar amountN'-methyl-N-cyclopropylamine, N-isopropyl-N'-cyclopropylamine,=N'-allyl-N-cyclopropylamine, N-propargyl-N'-cyclopropylamine,N'-phenethyl-N -cycl0propylamine, N-butyl-N-cyclopropylamine,N'-ethinyl-N'-cyclopropylamine, N-cinnamyl-N-cyclopropylamine,N-1-butiny1-N'-cyclopropylamine, N- l -propenyl-N-cyclopropylamine,N'-methyl-N'-2-phenylcyclopropylamine, N-methy1-N2- 3-trifluoromethyl)phenylcyclopropylamine, N'-allyl-N'-2- 4-fiuoro phenylcyclopropylamine,N'-propargyl-N'-2- 3 ,4-methylenedioxy phenylcyclopropylamine,N-benzyl-N'-2- (Z-methylthio phenylcyclopropylamine,Nmethyl-N'-2-benzylcyclopropylamine, N'-rnethyl-N-2- 4-trifiuoromethyl)phenylcyclopropylamine, N-benzyl-N'-2-benzylcyclopropylamine,N'-methyl-N-2-2-6-dichlorophenylcyclopropylamine andN-methyl-N'-2-2-methyl-4-trifluoromethylphenylcyclopropylamine,

there are obtained,

N'-methyl-N-cyclopropyl wchloroacetamide, N'-isopropyl-N'-cyc10propylot-chloroacetamide, N'-allyl-N'-cyclopropyl a-chloroacetamide,N'-propargyl-N-cyclopropyl a-chloroacetamide, N-phenethyl-N'-cyclopropylu-chloroacetamide, N'-butyl-N'-cyclopropyl a-chloroacetamide,N'-ethinyl-N-cyclopropyl a-chloroacetamide, N'-cinnamyl-N'-cyclopropyla-chloroacetamide, N-l-butinyl-N'-cyclopropyl a-chloroacetamide,N'-1-propenyl-N-cyclopropyl a-chloroacetamide,N'-methyl-N-Z-phenycyclopropyl ot-chloroacetamide,N-methyl-N'-2-3-trifluoromethylphenylcyclopropyl a-chloroacetamide,N'-allyl-N-2-4-fiuorophenylcyclopropyl ot-chloroacetamide,N-propargyl-N'-2-3,4-methylenedioxyphenylcyclopropyl a-chloroacetamide,

N-benzyl-N'-2-2-methylthiophenylcyclopropyl u-chloroacetamide,

N-methyl-N-2-benzylcyclopropyl ot-chloroacetamide,

N'-methyl-N'-2-4-trifluoromethylphenylcyclopropyl u-chloroacetamide,

N'-benzyl-N-2-benzylcylopr0pyl u-chloroacetamide,

N'-2-methyl-N-2-2,6-dichlorophenylcyclopropyl a-chloroacetamide andN'-rnethyl-N(-2-Z-methyl-4-trifluoromethylphenylcyclopropyla-chloroacetamide, respectively.

EXAMPLE 6 Preparation of m-(N-benzyl-N-methyl)-amino-N'-cyclopropylacetamide To a gently refluxing solution ofu-chloro-N'-cyclopropylacetamide (131 gm., 0.97 mol) and triethylarninegm.) in benzene (2 liters) was added dropwise N- methylbenzylamine gm.,1.0 mol). The solution was refluxed overnight, and upon cooling, thesalts were removed by filtration. Benzene was removed in vacuo to leavea residue of 226 gm. of crude ot-(N-benzyl-N- methyl)amino-N-cyclopropylacetamide.

A portion of the crude product was purified by distillation, B.P. C./0.2mm. On standing, the ot-N-benzyl- Nmethyl)-amino-N'-cyclopropylacetamide crystallized, and after washingwith petroleum ether, showed a melting point of 49-52" C., and infraredabsorption spectra as follows:

Preparation of N-benzyl-N-methyl-N'-cyclopropylethylenediamine max.

at (N benzyl N methyl)amino-N-cyclopropylacetamide, prepared in Example6, was dissolved in tetrahydrofuran (anhydrous) and added dropwise to asuspension of lithium aluminum hydride (43 gm.) in anhydroustetrahydrofuran (1 liter). After completion of the additon, the mixturewas refluxed with stirring for 3 hours to complete the reduction. Themixture was cooled in an ice bath and the excess lithium aluminumhydride was destroyed by the addition of a saturated aqueous so diumsulfate solution. Upon removal of the tetrahydrofuran in vacuo, an oilremained which was dissolved in ether, dried over anhydrous potassiumcarbonate and purified by fractional distillation, B.P. 7072 C./0.100.15mm., to yield 167 gm. ofN-benzyl-N-methyl-N'-cyclopropylethylenediamine.

EXAMPLE 8 Preparation of N-benzyl-N-methyl-N'-cyclopropylethylenediaminedihydrochloride N-benzyl N methyl-N'-cyclopropylethylenediamine,prepared in Example 7, was dissolved in ethanol, and converted to itsdihydrochloride by the addition of an excess of ethanolic HCl.

157 gm. of N-benZyl-N-methyl-N'-cyclopropylethylenediaminedihydrochloride were obtained having a melting point of 230-231" C., andthe following analysis: Calcd for C H Cl N (percent): C, 56.36; H, 8.01;N, 10.11; Cl, 25.60. Found (percent): C, 56.44; H, 8.73; N, 9.80; Cl,25.46.

1 5 EXAMPLE 9 Preparation of N-benzyl-N-methyl-N'-cyclopropyl-N'-formylethylenediamine To a chloroform solution containing N-benzyl-N-methyl N cyclopropylethylenediamine (8.0 gm., 0.022 mol) prepared inExample 7, was added chloral (5.3 gm.). The mixture was stirred at roomtemperature for 2 hours, and then refluxed for 1 hour. The chloroformwas removed by distillation, and 8.9 gm. of the product, N- benzyl Nmethyl N cyclopropyl-N'-formylethylenediamine, was collected byfractional distillation, B.P. 126130 C./0.2 mm., had an infraredabsorption spectrum as follows:

A523. 6.00, 13.60 and 1440 EXAMPLE 10 Preparation ofN-benzyl-N-cyclopropyl-N,N'-dirnethylethylenediarnine Ha Ha N benzyl Nmethyl N cyclopropyl N formylethylenediamine, prepared in Example 9, wasdissolved in tetrahydrofuran (anhydrous) and added dropwise to asuspension of lithium aluminum hydride (3.5 gm.) in anhydroustetrahydrofuran (1 liter). After completion of the addition, the mixturewas refluxed with stirring for 3 hours to complete the reduction. Themixture was cooled in an ice bath and the excess lithium aluminumhydride was destroyed by the addition of a saturated aqueous sodiumsulfate solution. Upon removal of the tetrahydrofuran in vacuo, 5.2 gm.of the product, Nbenzyl-N'- cyclopropyl-N,N-dimethylethylenediamine, wascollected by distillation, B.P. 95-100 C./0.2 mm., having an in fraredabsorption spectrum as follows:

X252, no band at. 6.00, band at 13.65 and 14.40;]. This indicatescomplete reduction of the formyl group.

EXAMPLE 11 Preparation of N-benzyl-N'-cyclopropyl-N,N-dimethylenediaminedihydrochloride N-benzyl N'-cyclopropyl N,N'-dimethylethylenediamine,prepared in Example 10, was converted to the dihydrochloride salt withgaseous HCl in ethanol, yielding 4.8 gm. ofN-benzyl-N-cyclopropyl-N,N'-dimethylethylenediamine dihydrochloride,which had a melting point of 117-119 C.

EXAMPLE 12 Preparation of N-benzyl-N-methyl-N-cyclopropy1-N'-propargylethylenediamine C HzCEGH To a refluxing solution (undernitrogen) of N-benzyl- N-methyl-N-cyclopropyl 1,2-diaminoethane (12.7gm., 0.062 mol) in tetrahydrofuran (100 ml.) was added dropwise 32.6 ml.of 2 N CH MgBr solution. After evolution of methane ceased, 7.4 gm.(0.062 mol) of propargyl bromide in benzene (150 ml.) was added to thereaction mixture and refluxed for 3 hours. The solution was treated withwater (100 ml.), the benzene layer was decanted, and the aqueous partwas extracted twice with benzene. After drying, the benzene was removedand the residue distilled. Material with a B.P. of 95-100 C./0.15 mm.,was collected, yielding 5.2 gm. of N-benzyl-N- methyl N-cyclopropyl Npropargylethylenediamine which had an infrared spectrum as follows:

A215; 3.05, 13.75 and 1440 EXAMPLE 13 Preparation ofN-benzyl-N-methyl-N-cyclopropyl-N- propargylethylenediaminedihydrochloride A213; 3.05, 13.45, 14.35, 14.80 and 15.70;

EXAMPLE 14 Preparation of a-(N-benzyl-N-methyl) amino-N-Z-phenylcyclopropylacetamide To a gently refluxing solution of 21.2 gm.(0.10 mol) of a-ChlOIO-N' Z-phenylcyclopropylacetamide and 11.0 gm.triethylamine in 250 cc. of benzene was added drop- Wise 14.3 gm. (0.11mol) of N-benzyl-N-methylamine and the solution refluxed for 20 hours.After removal of the salts and the benzene, the product, a-(N-benzyl-N-methyDamino N'-2 phenylcyclopropylacetamide, was subjected to reductionwithout further purification as shown in the subsequent example.

EXAMPLE 15 Preparation ofN-benzyl-N-methyl-N-2-phenylcyclopropylethylenediamine n @OHH -MEGHr-N4Ia-(N-benzyl-N-methyl)amino N-2-phenylcycloprop ylacetamide, prepared inExample 14, was dissolved in tetrahydrofuran (anhydrous) and addeddropwise to a suspension of lithium aluminum hydride (43 gm.) andanhydrous tetrahydrofuran (1 liter). After completion of the addition,the mixture was refluxed with stirring for 3 hours to complete thereduction. The mixture was cooled in an ice bath and the excess lithiumaluminum hydride was'destroyed by the addition of a saturated aqueoussodium sulfate solution. Upon removal of the tetrahydrofuran in vacuo,an oil remained which was dissolved in ether, dried over anhydrouspotassium carbonate and purified by fractional distillation, B.P. -118C./ 0.10 mm., to yield 15 gm., of N-benzyl-N-methyl-N'-Z-phenylcyclopropylethylenediamine.

EXAMPLE 16 Preparation of a-(N-m-trifluoromethylbenzyl-N-methyl)amino-N'-cyclpropylacetamide CH3 GFa u-Chloro-N'-cyclopropylacetamide isreacted with N- m-trifluoromethylbenzyl-N-methylamine (obtained from thereaction of m-chloromethylbenzotrifluoride and excess methylamine) inthe manner described in Example 25N-butenyl-N-propargyl-N-cyclopropylethylenediamine,N-propargyl-N-propargyl-N'-cyclopropylethylenediamine,N-cyclopropyl-N-propargyl-N-cyclopropylethylenediamine,N-methyl-N-ethinyl-N'-cyclopropylethylenediamine andN-methyl-N-butinyl-N-cyclopropylethylenediamine,

respectively.

EXAMPLE 26 When, in the procedure of Example 6, a-chloro-N'-chloropropylacetamide is replaced by an equal molar amount of 11-chloro-N'-benzyl-N-cyclopropylacetamide and N-methylbenzylamine isreplaced by an equal molar amount of N-methyl-N-propargylamine,N-ethinyl-N-propargylamine, N-isopropyl-N-propargylamine,N-allyl-N-propargylamine, N-butenyl-N-propargylamine,N-propargyl-N-propargylamine, N-cyclopropy1-N-propargylamine,N-methyl-N-ethinylamine and N-methyl-N-butinylamine,

there are obtained,

a-N-methyl-N-propargylamino-N-benzyl-N'-cyclopropylacetamide,a-N-ethinyl-N-propargylamino-N-benzyl-N'-cyclopropylacetamide,a-N-isopropyl-N-propargylamino-N'-benzyl-N'-cyclopropylacetamide,u-N-allyl-N-propargylamino-N'-benzyl-N-cyclopropylacetamide,a-N-butenyl-N-propargylamino-N-benzyl-N'-cyclopropylacetamide,ix-N-propargyl-N-propargylamino-N-benzyl-N'-cyclopropylacetamide,a-N-cyclopropyl-N-propargylamino-N'-benzyl-N'- cyclopropylacetamide,vt-N-methyl-N-ethinylamino-N'-benzyl-N'-cyclopropylacetamide anda-N-methyl-N-butinylamino-N'-benzyl-N'-cyclopropylacetamide,respectively.

EXAMPLE 27 When, in the procedure of Example 7, u-(N-benzyl-N-methyl)amino-N-cyclopropylacetamide is replaced by an equal molar amountof each of the products of Example 26, there are obtained,

N-methyl-N-propargyl-N-benzyl-N-cyclopropylethylenediamine,

N-ethinyl-N-propargyl-N'-benzyl-N'-cyclopropylethylenediamine,

N-isopropyl-N-propargyl-N '-benzyl-N-cyclopropylethylenediamine,

N-allyl-N-propargyl-N-benzyl-N-cyclopropylethylenediamine,

N-butenyl-N-propargyl-N-benzyl-N'-cyclopropylethylenediamine,

N-propargyl-N-propargyl-N-benzyl-N'-cyclopropy1- ethylenediamine,

N-cyclopropyl-N-propargyl-N'-benzyl-N-cyclopropylethylenediamine,

N-methyl-N-ethinyl-N'-benzyl-N '-cyclo pro pylethylenediamine andN-methyl-N-butinyl-N'-benzyl-N'-cyclopropylethylenediamine,respectively.

26 EXAMPLE 28 Preparation of a-(N-cyclopropyl-N-benzyl)-amin0-N-methylacetamide HA LHP anon maX' EXAMPLE 29N-methyl-N-benzyl-N'-cyclopropylethylenediamine on (N cyclopropyl Nbenzyl)amino-N'-methylacetamide, 33.7 gm., was reduced with 10 gm.lithium aluminum hydride in tetrahydrofuran by refluxing overnight.Excess lithium aluminum hydride was destroyed With saturated Na SOsolution and the tetrahydrofuran was removed by distillation atatmospheric pressure. The residue was distilled to yield a liquid,N-methyl-N-benzyl- N'-cyclopropylethylenediamine, B.P. l27l29.5/6 mm.;yield, 32.2 gm.

x213; No C=O A dihydrochloride was prepared with 6.0 gm. of the diaminefrom ethanolic HCl. Removal of solvent gave a gum which was crystallizedfrom ethanol-ether. The solid was recrystallized from ethanol-ether anddried in a dessicator. Yield, 5.5 gm. ofN-methyl-N'-benzyl-N-cyclopropylethylenediamine dihydrochloride, M.P.145-158 C.

Analysis.Calcd for C H N Cl (percent): C, 56.36; H, 8.01; N, 10.11; Cl,25.60. Found (percent): C, 56.16; H, 8.04; N, 10.26; Cl, 25.80.

EXAMPLE 30 Preparation of N-methyl-N-propargyl-N-benzyl-N'-cyclopropylethylenediamine hours refluxing, the solution was cooled, ml.water was added, and the benzene layer was decanted. The water layer wasagain extracted twice more with benzene and the benzene extracts weredried and made free of solvent. An oil, 16.7 gm., was obtained which Wasdistilled to yield 8.0 gm. of N-methyl-N-propargyl-N' benzyl-N'-cyclopropylethylenediamine; B.P. 99114/0.09 mm.

A crystalline dihydrochloride was obtained from ethanolether andrecrystallized from the same solvent system to yield 5.4 gm. ofN-methyl-N-propargyl-N'-benzyl-N'- cyclopropylethylenediaminedihydrochloride; M.P. 171- 174 C. with decomposition.

Thus, it is apparent from the foregoing description that the objects ofthis invention have been attained. Novel compounds have been inventedwhich have antidepressant activity and inhibit monoamine oxidase. Inaddition, a noval method of treating depression has been invented.

While this invention has been described and exemplified in terms of itspreferred embodiment, those skilled in the art will appreciate thatmodifications can be made without departing from the spirit and scope ofthis invention.

We claim:

1. A compound of the formula CH3 R 28 alkylene radical containing from 1to 4 carbon atoms, inclusive, alken represents a divalent alkenyleneradical containing from 2 to 4 carbon atoms, inclusive, and Phrepresents a ardical of the formula 3. A pharmaceutically acceptablenontoxic salt of the compound of claim 2.

References Cited UNITED STATES PATENTS 2,986,564 5/1961 Rips 260326.9 XR

ALEX MAZE, Primary Examiner J. A. NARCAVAGE, Assistant Examiner US. Cl.X.R.

mg UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Pgtgut no. 3,55,7 Dated October 6, 197G Inventct(g) John H. Biel and Edward J. WarawaIt is certified that error appears in the above-identified patent andthat said Letters Patent are hereby corrected as shown below:

In the Claims, Claim 1 should read:

2 CH R wherein R is a member selected from the group consistinr ofhydrogen, (lower)alkyl, (lower) alkanyl, zlower)alllcynyl, phenylalkyland phenylalkanyl; and R is hydrogen and the pharmaceutically acceptablenontoxic salts thereof.

SIGNED AND REALEB mam ( Atteal:

Edward M. Fletcher, Ir, WILLIAM E. W, m. LAnesfin Officer Patmtfl .J

